TNF-α converting enzyme (TACE) catalyzes the formation of TNF-α from membrane bound TNF-α precursor protein. TNF-α is a pro-inflammatory cytokine that is believed to have a role in rheumatoid arthritis [Shire, M. G.; Muller, G. W. Exp. Opin. Ther. Patents 1998, 8(5): 531; Grossman, J. M.; Brahn, E. J. Women's Health 1997, 6(6): 627; Isomaki, P.; Punnonen, J. Ann. Med. 1997, 29: 499; Camussi, G.; Lupia, E. Drugs, 1998, 55(5): 3] septic shock [Mathison et al. J. Clin. Invest. 1988, 81: 1925; Miethke et al. J. Exp. Med. 1992, 175: 91], graft rejection [Piguet, P. F. et al. J. Exp. Med. 1987, 166: 1280], cachexia [Beutler, B.; Cerami, A. Ann. Rev. Biochem. 1988, 57: 505], anorexia, inflammation [Ksontini, R. et al. Arch. Surg. 1998, 133: 558], congestive heart failure [Packer, M. Circulation, 1995, 92(6): 1379; Ferrari, R. et al. Circulation, 1995, 92(6): 1479], post-ischaemic reperfusion injury, inflammatory disease of the central nervous system, inflammatory bowel disease, insulin resistance [Hotamisligil, G. S. et al. Science, 1993, 259: 87] and HIV infection [Peterson, P. K. et al. J. Clin. Invest. 1992, 89: 574; Pallares-Trujillo, J. et al. Med. Res. Reviews, 1995, 15(6): 533], in addition to its well-documented antitumor properties [Old, L. Science, 1985, 230: 630]. For example, research with anti-TNF-α antibodies and transgenic animals has demonstrated that blocking the formation of TNF-α inhibits the progression of arthritis [Rankin, E. C. et al. Br. J. Rheumatol. 1995, 34: 334; Pharmaprojects, 1996, Therapeutic Updates 17(Oct.), au197-M2Z]. This observation has recently been extended to humans as well [“TNF-α in Human Diseases”, Current Pharmaceutical Design, 1996, 2: 662].
Because of the link between TNF-α and various disease states, it is expected that small molecule inhibitors of TACE/MMP would have the potential for treating such diseases. However, although a variety of TACE inhibitors are known, many of these molecules are peptidic and peptide-like, which suffer from bioavailability and pharmacokinetic problems. In addition, many of these molecules are non-selective, being potent inhibitors of matrix metalloproteinases and, in particular, MMP-1. Inhibition of MMP-1 (collagenase 1) has been postulated to cause joint pain in clinical trials of MMP inhibitors [Scrip, 1998, 2349: 20]. Long acting, selective, orally bioavailable non-peptide inhibitors of TACE would thus be highly desirable for the treatment of the disease states discussed above. The present invention is directed to these, as well as other, important ends